Project Summary/Abstract Infertility is a common disease, which affects 1.5 million women each year in the United States. It is heterogeneous in both etiology and severity, with different biologic mechanisms causing different types of infertility. While women suffering from infertility are known to have a higher risk of many adverse pregnancy outcomes, research suggests that these women may also be at increased risk of chronic diseases later in life, and NIH has prioritized the need to understand infertility as a potential marker for a woman?s overall health (PA- 17-091, ?Fertility Status as a Marker for Overall Health?). Prior research on the long-term health of women with infertility has been limited by studies with short duration of follow-up, low statistical power, and inability to take heterogeneity of infertility diagnoses, fertility treatment, and chronic diseases into account. Our proposal combines extensive phenotypic data from 116,430 participants Nurses? Health Study II collected prospectively over 30 years of follow-up, biologic samples, and genetic data to address these gaps in the existing literature. Our long-term goal is to understand whether women who have experienced infertility have adverse long-term health compared to women who never experienced infertility and the factors that underlie these differences. Our specific aims will address: Aim 1: Chronic disease incidence: Evaluate the relationship between infertility (overall and by subtype) and the risk of cardiovascular diseases (myocardial infarction and stroke), type 2 diabetes, and breast cancer. Aim 2: Biomarkers of chronic disease: Investigate whether women who experienced infertility have altered inflammatory, cardiometabolic, and hormonal biomarker profiles compared to women who have not experienced infertility. Aim 3: Shared genetics: Evaluate whether women experiencing infertility have a different genetic profile compared to women never experiencing infertility using bi-directional mendelian randomization. No studies have utilized these combined phenotypic, biologic, and genetic data at the scale required to address fundamental public health questions related to the long-term health of women with infertility ? a scientific gap that we address in this proposal. As approximately one in six women experience infertility, the potential public health impact of understanding the relationship between infertility and long-term health demands pursing research in this area. These aims represent a rigorous and efficient opportunity to investigate infertility in relation to women?s overall long-term health trajectory.